EP2799437A1 - Chinolin- und cinnolinverbindungen und ihre verwendung - Google Patents
Chinolin- und cinnolinverbindungen und ihre verwendung Download PDFInfo
- Publication number
- EP2799437A1 EP2799437A1 EP12862344.4A EP12862344A EP2799437A1 EP 2799437 A1 EP2799437 A1 EP 2799437A1 EP 12862344 A EP12862344 A EP 12862344A EP 2799437 A1 EP2799437 A1 EP 2799437A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- phenyl
- methoxy
- fluoro
- oxo
- oxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 title abstract description 19
- 125000000259 cinnolinyl group Chemical class N1=NC(=CC2=CC=CC=C12)* 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 97
- 150000003839 salts Chemical class 0.000 claims abstract description 44
- 239000000651 prodrug Substances 0.000 claims abstract description 35
- 229940002612 prodrug Drugs 0.000 claims abstract description 35
- 239000012453 solvate Substances 0.000 claims abstract description 32
- 150000004677 hydrates Chemical class 0.000 claims abstract description 31
- 239000003814 drug Substances 0.000 claims abstract description 15
- 238000002360 preparation method Methods 0.000 claims abstract description 15
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 14
- 201000011510 cancer Diseases 0.000 claims abstract description 11
- 238000011282 treatment Methods 0.000 claims abstract description 7
- -1 cyano, carboxyl Chemical group 0.000 claims description 63
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 40
- 125000003545 alkoxy group Chemical group 0.000 claims description 34
- 229910052736 halogen Inorganic materials 0.000 claims description 33
- 150000002367 halogens Chemical class 0.000 claims description 33
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 21
- 229910052717 sulfur Inorganic materials 0.000 claims description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
- 125000004185 ester group Chemical group 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 125000005257 alkyl acyl group Chemical group 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 10
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 201000005202 lung cancer Diseases 0.000 claims description 9
- 208000020816 lung neoplasm Diseases 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims description 8
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 8
- 125000006728 (C1-C6) alkynyl group Chemical group 0.000 claims description 8
- 125000004414 alkyl thio group Chemical group 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 8
- 206010009944 Colon cancer Diseases 0.000 claims description 7
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 7
- 208000029742 colonic neoplasm Diseases 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 206010017758 gastric cancer Diseases 0.000 claims description 5
- GKOQMHKEJBDRPQ-UHFFFAOYSA-N n-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-4-oxo-1-[2-(trifluoromethyl)phenyl]cinnoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCN(C)CC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=NN1C1=CC=CC=C1C(F)(F)F GKOQMHKEJBDRPQ-UHFFFAOYSA-N 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- LROMRGVLIPZFTD-UHFFFAOYSA-N 1-(2-chlorophenyl)-n-[3-fluoro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-yl]oxyphenyl]-4-oxoquinoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCCC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=CN1C1=CC=CC=C1Cl LROMRGVLIPZFTD-UHFFFAOYSA-N 0.000 claims description 4
- ZZUMPERXQGCPQG-UHFFFAOYSA-N 1-(2-chlorophenyl)-n-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperidin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-4-oxoquinoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCC(C)CC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=CN1C1=CC=CC=C1Cl ZZUMPERXQGCPQG-UHFFFAOYSA-N 0.000 claims description 4
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- CRJCEBJOXSNPCW-UHFFFAOYSA-N n-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-1-(2-fluorophenyl)-4-oxoquinoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCN(C)CC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=CN1C1=CC=CC=C1F CRJCEBJOXSNPCW-UHFFFAOYSA-N 0.000 claims description 4
- VFBUFCATGQLMQE-UHFFFAOYSA-N n-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperidin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-1-(2-fluorophenyl)-4-oxoquinoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCC(C)CC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=CN1C1=CC=CC=C1F VFBUFCATGQLMQE-UHFFFAOYSA-N 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- LJBKLMNKABTRLH-UHFFFAOYSA-N 1-(2,4-dichlorophenyl)-n-[3-fluoro-4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinolin-4-yl]oxyphenyl]-4-oxocinnoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCCCC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=NN1C1=CC=C(Cl)C=C1Cl LJBKLMNKABTRLH-UHFFFAOYSA-N 0.000 claims description 3
- JRRSPFNGDMSCBH-UHFFFAOYSA-N 1-(2,4-dichlorophenyl)-n-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-4-oxocinnoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCN(C)CC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=NN1C1=CC=C(Cl)C=C1Cl JRRSPFNGDMSCBH-UHFFFAOYSA-N 0.000 claims description 3
- AITZJXZPVHHUES-UHFFFAOYSA-N 1-(2,4-dimethylphenyl)-n-[3-fluoro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-yl]oxyphenyl]-4-oxocinnoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCCC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=NN1C1=CC=C(C)C=C1C AITZJXZPVHHUES-UHFFFAOYSA-N 0.000 claims description 3
- HMSXVOPSMANGEQ-UHFFFAOYSA-N 1-(2,4-dimethylphenyl)-n-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-4-oxocinnoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCN(C)CC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=NN1C1=CC=C(C)C=C1C HMSXVOPSMANGEQ-UHFFFAOYSA-N 0.000 claims description 3
- YGEMLCGGRQUBCT-UHFFFAOYSA-N 1-(2,4-dimethylphenyl)-n-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperidin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-4-oxocinnoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCC(C)CC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=NN1C1=CC=C(C)C=C1C YGEMLCGGRQUBCT-UHFFFAOYSA-N 0.000 claims description 3
- UNUOJJJJMNFSAC-UHFFFAOYSA-N 1-(2,6-dichlorophenyl)-n-[3-fluoro-4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinolin-4-yl]oxyphenyl]-4-oxocinnoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCCCC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=NN1C1=C(Cl)C=CC=C1Cl UNUOJJJJMNFSAC-UHFFFAOYSA-N 0.000 claims description 3
- YXHJZCCPKMMPDW-UHFFFAOYSA-N 1-(2,6-dichlorophenyl)-n-[3-fluoro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-yl]oxyphenyl]-4-oxocinnoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCCC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=NN1C1=C(Cl)C=CC=C1Cl YXHJZCCPKMMPDW-UHFFFAOYSA-N 0.000 claims description 3
- KZGYLXSFALYNHR-UHFFFAOYSA-N 1-(2,6-dichlorophenyl)-n-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-4-oxocinnoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCN(C)CC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=NN1C1=C(Cl)C=CC=C1Cl KZGYLXSFALYNHR-UHFFFAOYSA-N 0.000 claims description 3
- PAGRSZZWQKPHIC-UHFFFAOYSA-N 1-(2,6-dichlorophenyl)-n-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperidin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-4-oxocinnoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCC(C)CC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=NN1C1=C(Cl)C=CC=C1Cl PAGRSZZWQKPHIC-UHFFFAOYSA-N 0.000 claims description 3
- FZRUQGYVXOSMMR-UHFFFAOYSA-N 1-(2-bromo-4-fluorophenyl)-n-[3-fluoro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-yl]oxyphenyl]-4-oxocinnoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCCC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=NN1C1=CC=C(F)C=C1Br FZRUQGYVXOSMMR-UHFFFAOYSA-N 0.000 claims description 3
- NPIGUQPJANYHON-UHFFFAOYSA-N 1-(2-bromo-4-fluorophenyl)-n-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-4-oxocinnoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCN(C)CC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=NN1C1=CC=C(F)C=C1Br NPIGUQPJANYHON-UHFFFAOYSA-N 0.000 claims description 3
- IZYHSADOCZKLPU-UHFFFAOYSA-N 1-(2-bromophenyl)-n-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-4-oxocinnoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=NN1C1=CC=CC=C1Br IZYHSADOCZKLPU-UHFFFAOYSA-N 0.000 claims description 3
- JOKCZZZFNZGZAR-UHFFFAOYSA-N 1-(2-bromophenyl)-n-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-4-oxocinnoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCN(C)CC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=NN1C1=CC=CC=C1Br JOKCZZZFNZGZAR-UHFFFAOYSA-N 0.000 claims description 3
- WTAUZZCXDFWWIR-UHFFFAOYSA-N 1-(2-chlorophenyl)-n-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-4-oxoquinoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCN(C)CC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=CN1C1=CC=CC=C1Cl WTAUZZCXDFWWIR-UHFFFAOYSA-N 0.000 claims description 3
- IVXLTIGAKFHGRU-UHFFFAOYSA-N 1-(3,4-difluorophenyl)-n-[3-fluoro-4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinolin-4-yl]oxyphenyl]-4-oxocinnoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCCCC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=NN1C1=CC=C(F)C(F)=C1 IVXLTIGAKFHGRU-UHFFFAOYSA-N 0.000 claims description 3
- AXAVUZNLMMIUEI-UHFFFAOYSA-N 1-(3,4-difluorophenyl)-n-[3-fluoro-4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinolin-4-yl]oxyphenyl]-4-oxoquinoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCCCC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=CN1C1=CC=C(F)C(F)=C1 AXAVUZNLMMIUEI-UHFFFAOYSA-N 0.000 claims description 3
- QDZNZFNADWFZJG-UHFFFAOYSA-N 1-(3,4-difluorophenyl)-n-[3-fluoro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-yl]oxyphenyl]-4-oxocinnoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCCC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=NN1C1=CC=C(F)C(F)=C1 QDZNZFNADWFZJG-UHFFFAOYSA-N 0.000 claims description 3
- WINZETBOPROFDC-UHFFFAOYSA-N 1-(3,4-difluorophenyl)-n-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperidin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-4-oxoquinoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCC(C)CC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=CN1C1=CC=C(F)C(F)=C1 WINZETBOPROFDC-UHFFFAOYSA-N 0.000 claims description 3
- GEVJPYJFUVGELI-UHFFFAOYSA-N 1-(4-bromophenyl)-n-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-4-oxocinnoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=NN1C1=CC=C(Br)C=C1 GEVJPYJFUVGELI-UHFFFAOYSA-N 0.000 claims description 3
- NIJGFCFIXFXMBX-UHFFFAOYSA-N 1-(4-bromophenyl)-n-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-4-oxocinnoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCN(C)CC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=NN1C1=CC=C(Br)C=C1 NIJGFCFIXFXMBX-UHFFFAOYSA-N 0.000 claims description 3
- JYQLVVOBTMGKEW-UHFFFAOYSA-N 1-[2-chloro-5-(trifluoromethyl)phenyl]-n-[3-fluoro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-yl]oxyphenyl]-4-oxocinnoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCCC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=NN1C1=CC(C(F)(F)F)=CC=C1Cl JYQLVVOBTMGKEW-UHFFFAOYSA-N 0.000 claims description 3
- ZCPIUELMTNNKQI-UHFFFAOYSA-N 1-[2-chloro-5-(trifluoromethyl)phenyl]-n-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-4-oxocinnoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCN(C)CC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=NN1C1=CC(C(F)(F)F)=CC=C1Cl ZCPIUELMTNNKQI-UHFFFAOYSA-N 0.000 claims description 3
- TUKCSABDIUZQKJ-UHFFFAOYSA-N 1-[2-chloro-5-(trifluoromethyl)phenyl]-n-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperidin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-4-oxocinnoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCC(C)CC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=NN1C1=CC(C(F)(F)F)=CC=C1Cl TUKCSABDIUZQKJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 3
- SLONUMXPVJUXEW-UHFFFAOYSA-N n-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-4-oxo-1-[2-(trifluoromethoxy)phenyl]cinnoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=NN1C1=CC=CC=C1OC(F)(F)F SLONUMXPVJUXEW-UHFFFAOYSA-N 0.000 claims description 3
- XVCAWUDBPPTHLF-UHFFFAOYSA-N n-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-4-oxo-1-[2-(trifluoromethyl)phenyl]quinoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=CN1C1=CC=CC=C1C(F)(F)F XVCAWUDBPPTHLF-UHFFFAOYSA-N 0.000 claims description 3
- YATXWCOZSJKGDF-UHFFFAOYSA-N n-[3-fluoro-4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinolin-4-yl]oxyphenyl]-4-oxo-1-[2-(trifluoromethoxy)phenyl]cinnoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCCCC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=NN1C1=CC=CC=C1OC(F)(F)F YATXWCOZSJKGDF-UHFFFAOYSA-N 0.000 claims description 3
- RIJAXDHUBFBQQH-UHFFFAOYSA-N n-[3-fluoro-4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinolin-4-yl]oxyphenyl]-4-oxo-1-[3-(trifluoromethyl)phenyl]cinnoline-3-carboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCCCC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C(C1=CC=CC=C11)=O)=NN1C1=CC=CC(C(F)(F)F)=C1 RIJAXDHUBFBQQH-UHFFFAOYSA-N 0.000 claims description 3
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- 238000002798 spectrophotometry method Methods 0.000 description 1
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- 201000000498 stomach carcinoma Diseases 0.000 description 1
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- 239000001117 sulphuric acid Substances 0.000 description 1
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- 239000000375 suspending agent Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
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- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
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- 229940099259 vaseline Drugs 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to a new series of quinoline and cinnoline derivatives, pharmaceutically acceptable salts, hydrates, solvates or prodrugs and the processes for their preparation and pharmaceutical compositions containing the compounds.
- said quinoline and cinnoline derivatives shows potent inhibitory activity against c-Met kinase.
- the present invention further relates to the uses of the compounds, pharmaceutically acceptable salts, hydrates, solvates or prodrugs for the preparation of medicaments for the treatment and/or prevention of diseases caused by abnormal expression of c-Met kinase, especially for treatment and/or prevention of cancer.
- Cancer is a serious hazard to human life and health. With the changes of external factors such as environmental pollution, the number of cancer cases is rising year by year. According to World Health Organization statistics, about 10 million tumor patients are diagnosed worldwide each year currently, and 7 million people die of cancer related diseases, therefore, malignant tumor has become human's second largest killer which is second only to cardiovascular disease.
- Protein kinase a kind of enzyme, catalyzes phosphorylation of hydroxyl on tyrosine, serine, and threonine residues through the transfer of the end of ATP (y) phosphate. Through signal transduction pathways, these enzymes regulate cell growth, differentiation and proliferation. Therefore, all aspects of cell cycle are dependent on the activity of PKs substantially. Furthermore, PKs abnormal activity is associated with the host of disease, ranging from relatively non-life threatening diseases (e.g.: psoriasis) to extremely fatal diseases (e.g., glioblastoma). Protein kinases include two types: Protein tyrosine kinase (PTK) and Serine-threonine kinase (STK).
- PTK Protein tyrosine kinase
- STK Serine-threonine kinase
- PTK activity is to participate as cell-surface protein growth factor receptor.
- the growth factor receptor turns into an activated form, which interacts with the protein on the inner surface of cell membrane, through combining with growth factor ligand. It leads to phosphorylation of receptor and other protein tyrosine residue, and the formation of multiple cytoplasmic signaling molecule complexes which affects cell reaction, such as division (proliferation), differentiation, growth, metabolism etc.
- RTK receptor tyrosine kinase
- Met is one of the members of this family, and is often referred to as c-Met or human hepatocyte growth factor receptor tyrosine kinase (hHGFR).
- c-Met human hepatocyte growth factor receptor tyrosine kinase
- hHGFR human hepatocyte growth factor receptor tyrosine kinase
- c-Met Stimulated by ligand HGF (also known as Scatter Factor), c-Met starts a variety of physiological processes containing cell proliferation, motility, differentiation, angiogenesis, wound healing, tissue regeneration, embryonic development. Stimulation of hepatocyte growth factor makes c-Met receptor rapidly internalized via clathrin coated vesicles, and gather around cell nucleus by early transportation of endosomes cavity.
- HGF also known as Scatter Factor
- c-Met Down regulation, dysregulation, overexpression, mutation of c-Met and/or HGF are associated with uncontrolledcell proliferation and survival, which plays an important role in tumor cell invasion, growth and migration in the early. For this reason, c-Met becomes an important target for anticancer drug development.
- Patents ( US 2005/0037431 and US 2004/0166544 ) describe the inhibition of c-Met in tumor xenotransplantation mouse model to slow down the growth of tumor, and the specific antibodies for c-Met have been expression to block the binding of HGF to c-Met.
- the Overexpression of c-Met is also occurred in NSCLC, small cell lung cancer, lung cancer cell, breastcancer cell, coloncancer cell and Prostate cancer cell. Because c-Met seems to play an important role in the formation of multiple tumors, a variety of strategies have been used to inhibit this receptor tyrosine kinase.
- HGF ⁇ chain binding to c-Met can affect the regulation of HGF/c-Met signaling pathway.
- zymogen form HGF ⁇ mutant shows 14 times lower affinity to c-Met than to wild-type serine protease form, which suggests that comformational change in singlestranded form of cleaved can lead to best interaction.
- the extensive mutation of active site of serine protease and the active area of HGF ⁇ show that among 38 purified double stranded HGF mutants, there are 17 damaged cells moving or phosphorylated but combining with c-Met.
- the decrease of biological activity is associated with the decrease of c-Met binding to its own mutant HGF ⁇ mutant, and the elimination of the dominant role of ⁇ - chain binding.
- Foretinib (Fig.l), reported as a quinoline compounds, is an oral c-Met and VEGFR/KDR kinase inhibitor with IC 50 values of 0.4 and 0.8nM to c-Met and KDR, respectively, and has entered phase II clinical research stage. Clinical studies have shown that, Foretinib showed a significant inhibitory effect against a variety of human tumor cell lines (such as human lung cancer cells, human gastric cancer cells, etc.), with an IC 50 values of 0.004 ⁇ g/mL.
- human tumor cell lines such as human lung cancer cells, human gastric cancer cells, etc.
- the present invention relates to a series of quinoline and cinnoline derivatives of general formula I, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, wherein:
- the term "pharmaceutically acceptable salts" as used herein refer to a pharmaceutically acceptable salt formed by quinoline and cinnoline derivatives defined as formula I reacted with acid.
- the acid includes inorganic or organic acids, and those salts formed by using the following acids are especially preferable: hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid,oxalicacid, tartaric acid or benzoic acid.
- the present invention includes the prodrugs of the derivatives of present invention.
- the prodrugs are the derivatives of general formula I, and the prodrugs have low biological activity or even have no biological activity, but which can be converted to a corresponding biologically-active form (e.g. by metabolism, solvolysis or other ways) under physiological conditions upon administration.
- the present invention includes the prodrugs of the derivatives of present invention.
- the prodrugs are the derivatives of general formula I, and the prodrugs have low biological activity or even have no biological activity, but which can be converted to a corresponding biologically-active form (e.g. by metabolism, solvolysis or other ways) under physiological conditions upon administration.
- halogen refers to fluorine, chlorine, bromine or iodine atom
- alkyl refers to a straight or branched alkyl
- alkylene refers to a straight or branched alkylene
- cycloalkyl refers to substituted or unsubstituted cycloalkyl
- aryl refers to unsubstituted or substituted phenyl
- heteroaryl comprises one or more heteroatoms selected from O, N and S, and may be one or more rings, and the ring system is aromatic and can be exemplified by imidazolyl, pyridinyl, pyrazolyl, (1, 2, 3)- and (1, 2, 4)-triazolyl, furanyl, thienyl, pyrrolyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, naphthyl, quinolyl, iso
- Saturated or partially saturated heterocyclic group refers to groups containing one or more heteroatoms selected from N, O, S monocyclic or polycyclic ring system , such as pyrrolidinyl, morpholinyl , piperazinyl, , piperidinyl , pyrazolidinyl , imidazolidinyl and thiazolyl group.
- the present invention further relates to a pharmaceutical composition, comprising quinoline and cinnoline derivatives as shown by general formula I, and pharmaceutically acceptable salts, hydrates, solvates or produg thereof as active ingredient, and pharmaceutically acceptable carrier or excipients if necessary.
- the pharmaceutically acceptable excipients refer to any diluents, adjuvants and/carrier that can be usable in pharmaceutical field.
- the derivatives in this present invention can be combined with other active ingredients as long as they are not deleterious to the recipient thereof, such as allergic action.
- quinoline and cinnoline derivatives of formula I required to be effective, will, of course, be varied. The factors to be considered include the therapeutic efficacy and bioavailability in vivo of the active ingredients, the rate of metabolism and discretion of them, the patient's age, sex and the period of disease. However, a suitable effective dose is in the range of about 10 to 1000 mg per day, preferably in the range about 50 to 500 mg per day. So,When the pharmaceutical compositions of the invention are formulated in a unit dosage form, considering the effective dose mentioned above, the amount of quinoline and cinnoline derivatives of formula I contained in each unit of pharmaceutical preparation is in the range of about 10 to 500 mg , preferably in the range of about 50 to 300 mg. According to the instructions of doctors or physician, the preparation can be administered several times at intervals (preferable once to six times).
- the pharmaceutical composition of present invention could be prepared into various formulations comprising several excipients commonly used in the pharmaceutical art, for example, injectable formulation, tablet, capsule, aerosol, suppository, membrane, guttate pills, linimentum, ointment and so on.
- the carrier useful for the pharmaceutical composition of present invention is those commonly used in the pharmaceutical field, including adhesive, lubricant, disintegrating agent, cosolvent, diluents, stabilizer, suspending agent, pigment, flavoring agent, preservatives, diluentsand matrix.
- the pharmaceutical formulation may be administrated by oral or parenteral pathway (e.g. intravenous, subcutaneous, intraperitoneal or topical), and could be prepared into enteric coated tablet in case some medicines are unstable in the conditions of stomach.
- the active compounds or pharmaceutically acceptable salts or solvates of the present invention thereof can be used for the only antiproliferative drug alone, or be combined with already listed antiproliferative drug for the treatment and/or prevention of proliferative diseases, such as psoriasis, benign prostatic hypertrophy, atherosclerosis and restenosis.
- proliferative diseases such as psoriasis, benign prostatic hypertrophy, atherosclerosis and restenosis.
- the compounds of present invention have an inhibitory activity on tumor cell growth.
- the compounds can be useful for the preparation of medicaments for treating and/or preventing cancer diseases, such as breast, lung, liver, kidney, colon, rectum, stomach, prostate, bladder, uterus, pancreas, bone marrow, testes, ovaries, lymph node, soft tissue, head and neck, thyroid, esophageal, leukemia, neurocytoma and so on.
- compounds of the present invention showed significant inhibition on lung cancer, colon cancer and gastric cancer cell lines. Therefore, the said compounds can be especially useful for the preparation of medicaments for treating and/or preventing of lung cancer and colon cancer.
- compounds of the present invention showed significant inhibition to c-Met kinase, and showed potent inhibition to lung cancer cells, colon cancer cells with high expression of c-Met. Therefore, the said compounds can be especially useful for the preparation of medicaments for treating and/or preventing of lung cancer.
- the active compounds, pharmaceutically acceptable salts or solvates of the present invention may be used as a single anticancer medicament, or used in combination with anticancer drugs listed (Platinum drug, cisplatin; camptothecin drug irinotecan; vinca alkaloid drug, Navelbine; deoxycytidine celecoxib drug, gemcitabine; etoposide, paclitaxel, etc.).
- anticancer drugs listed Platinum drug, cisplatin; camptothecin drug irinotecan; vinca alkaloid drug, Navelbine; deoxycytidine celecoxib drug, gemcitabine; etoposide, paclitaxel, etc.
- Route 1 illustrates the preparation of the compounds of general formula I of the present invention, wherein all starting materials can be prepared by the methods depicited in the Schemes or the methods well known to one of ordinary skill in the organic chemistry art, or are commercially available. All of the final compounds of the present invention are prepared by the methods depicited in the Schemes or similar methods, and these methods are well known to one of ordinary skill in the organic chemistry art. All variable factors as involved in these Schemes are defined as follows or defined as in claims.
- HNMR nuclear magnetic resonance hydrogen spectrum
- MS mass spectrum
- Example -NR 1 R 2 Y Z R 3 Ar Example 1 N CH H Example 2 N CH H Example 3 N CH H Example 4 N CH H Example 5 N CH F Example 6 N CH H Example 7 N CH H Example 8 N CH H Example9 N CH H Example 10 N CH H Example 11 N CH H Example 12 N CH H Example 13 N CH H Example 14 N CH H Example 15 N CH H Example 16 N CH H Example 17 N CH H Example 18 N CH H Example 19 N CH H Example 20 N CH H Example 21 N CH H Example 22 N CH H Example 23 N CH H Example 24 N CH H Example 25 N CH H Example 26 N CH H Example 27 N CH H Example 28 N CH H Example 29 N CH H Example 30 N CH H Example 31 N CH H Example 32 N CH H Example 33 N CH H Example 34 N CH H Example 35 N CH H Example 36 N CH H Example 37 N CH H Example 38 N CH H Example 39 N CH H Example 40 N CH H Example 41 N CH H Example 42 N CH H Example 43 N CH H Example 44 N CH F Example 45 N CH F Example 46 H CH H Example 47 H CH H Example 48 H CH H Example
- substituted intermediate Q-1 can be obtained by four steps including diazotization using different-substituted phenyl amine and intermediate c , which reacts with different-substituted M-1 to give compounds 2-45.
- substituted intermediate Q-2 can be obtained by reaction using intermediate c and DMF-DMA, followed by four steps with substituted phenyl amine, which reacts with substituted M-1 to give compound 47-60.
- intermediate III 72 g, 0.25 mol
- Iron powder 112 g, 2 mol
- hydrochloric acid 2 mL
- the reaction mixture was filtered without cooling, the filarate was cooled to room temperature to give precipitate, which was filtered to get off white solid 45 g.Yield: 70%.
- substituted M-2 can be synthesized by five steps containing reduction, cyclization reaction with intermediate III as starting material, which then reacts with substituted Q-1 to get compound 62-70.
- quinoline and cinnoline derivatives described as fomular I in this patent was evaluated against the cancer cell lines H460 (human lung cancer cell), HT-29 (colon cancer cell), U87MG (Human malignant glioblastoma cells), MKN-45 (human gastric carcinoma cell), SMMC-7721 (hepatoma cell).
- the compounds 50 pM c-Met (His-tagged recombinant human Met (Amino acids 974-ends), by baculovirus expression) and 5 ⁇ M ATP in buffer solution (25 mM MOPS, pH 7.4, 5 mM MgCl2, 0.5 raM MnCl 2 , 100 ⁇ M sodium orthovanadate, 0.01% Triton X-100, 1 mM DTT, 1% of DMSO1% (v/v)) was added, the solution was incubated for 20 min.
- buffer solution 25 mM MOPS, pH 7.4, 5 mM MgCl2, 0.5 raM MnCl 2 , 100 ⁇ M sodium orthovanadate, 0.01% Triton X-100, 1 mM DTT, 1% of DMSO1% (v/v)
- reaction mixture was removed by washing with 0.2 ⁇ g/mL conjugated horseradish peroxidase (HRP) monoclonal antibody specific for phosphotyrosine (PY20) detecting phosphorylation of the substrate polymer. 1M phosphoric acid was added to terminate the color, the chromogenic substrate (TMB) was tested by spectrophotometry at 450 nm.
- HRP horseradish peroxidase
- TMB chromogenic substrate
- Example c-Met IC 50 ( ⁇ g/mL)
- Example c-Met IC 50 ( ⁇ g/mL)
- Example c-Met IC 50 ( ⁇ g/mL)
- Example 1 0.05
- Example 26 0.3
- Example 51 0.2
- Example 2 0.03
- Example 27 0.4
- Example 52 1.6
- Example 3 0.2
- Example 28 1.3
- Example 53 0.5
- Example 4 0.6
- Example 29 Example 54 0.7
- Example 5 0.4 Example 30 0.6
- Example 55 0.9
- Example 6 0.8
- Example 31 0.2
- Example 56 0.1
- Example 7 0.5
- Example 32 0.1
- Example 57 0.8
- Example 9 0.3
- Example 33 1.1
- Example 10 0.01
- Example 35 1.1
- Example 60 0.29
- Example 11 0.03
- Example 36 0.67
- Example 63 0.8
- Example 12 0.1
- Example 37 0.69
- Example 65 0.68 Example 13 1.1
- Example 38 1.1
- the protected compounds in formula I in this invention have good anti-tumor activity in vitro, and are better than the anticancer drug cisplatin.
- Compounds of Formula I in the invention may be used alone, but usually given with a pharmaceutically acceptable carrier, which is selected according to the desired route of administration and standard pharmaceutical practice, the following preparation methods of such various pharmaceutical dosages (tablets, capsules, injections, aerosols, suppositories, films, pills, liniment, topical ointments) were used to describe new application in the pharmaceutical field.
- a pharmaceutically acceptable carrier which is selected according to the desired route of administration and standard pharmaceutical practice, the following preparation methods of such various pharmaceutical dosages (tablets, capsules, injections, aerosols, suppositories, films, pills, liniment, topical ointments) were used to describe new application in the pharmaceutical field.
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CN102643268B (zh) * | 2011-12-30 | 2014-05-21 | 沈阳药科大学 | 喹啉类及噌啉类化合物及其应用 |
CN104072480B (zh) * | 2013-03-27 | 2016-12-28 | 沈阳药科大学 | 喹啉类化合物及其制备方法和应用 |
CN103709145B (zh) * | 2013-12-27 | 2016-09-28 | 沈阳药科大学 | 含六氢嘧啶酮的喹啉类化合物及其制备方法和应用 |
CN105461687B (zh) * | 2014-08-26 | 2020-06-19 | 北京京奉医药科技有限公司 | 含二氢哒嗪酮的喹啉类化合物及其用途 |
CN106467541B (zh) * | 2015-08-18 | 2019-04-05 | 暨南大学 | 取代喹诺酮类衍生物或其药学上可接受的盐或立体异构体及其药用组合物和应用 |
JP6740354B2 (ja) | 2015-10-05 | 2020-08-12 | ザ トラスティーズ オブ コロンビア ユニバーシティー イン ザ シティー オブ ニューヨーク | オートファジーの流れ及びホスホリパーゼd及びタウを含むタンパク質凝集体のクリアランスの活性化剤ならびにタンパク質症の治療方法 |
CN107151240A (zh) * | 2016-03-04 | 2017-09-12 | 中国科学院上海药物研究所 | 一类多取代喹诺酮类化合物及其制备方法和用途 |
CN108530426A (zh) * | 2017-03-02 | 2018-09-14 | 沈阳药科大学 | 含喹喔啉酮的4-苯氧基取代喹啉类化合物及其应用 |
IL277671B2 (en) * | 2018-03-30 | 2024-03-01 | Haihe Biopharma Co Ltd | Quinoline (QUINOLINE) and quinazoline (QUINAZOLINE) compounds and their applications |
CN111196814B (zh) * | 2018-11-19 | 2022-12-06 | 北京赛特明强医药科技有限公司 | 芳环连二噁烷并喹唑啉或喹啉类化合物、组合物及其应用 |
EP3982965A4 (de) * | 2019-06-12 | 2023-01-25 | Praxis Biotech LLC | Modulatoren des integrierten stressreaktionsweges |
WO2021046515A1 (en) | 2019-09-06 | 2021-03-11 | Board Of Regents, The University Of Texas System | Inhibitors of receptor interacting protein kinase i for the treatment of disease |
CA3155259A1 (en) | 2019-09-27 | 2021-04-01 | Board Of Regents, The University Of Texas System | Inhibitors of receptor interacting protein kinase i for the treatment of disease |
JP2023502514A (ja) * | 2019-11-26 | 2023-01-24 | ボード オブ レジェンツ,ザ ユニバーシティ オブ テキサス システム | 疾患の処置のための受容体相互作用プロテインキナーゼiの阻害剤 |
CN111303121A (zh) * | 2020-04-20 | 2020-06-19 | 辽宁大学 | 含喹喔啉酮的4-苯氧基吡啶类化合物及其应用 |
CN115960054A (zh) * | 2022-12-15 | 2023-04-14 | 南通常佑药业科技有限公司 | 一种依泽替米贝中间体的制备方法 |
Family Cites Families (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2225555A1 (en) * | 1995-08-02 | 1997-02-13 | Chiroscience Limited | Quinolones and their therapeutic use |
AU1302301A (en) * | 1999-11-08 | 2001-06-06 | Sankyo Company Limited | Nitrogenous heterocycle derivatives |
DE60233736D1 (de) * | 2001-06-22 | 2009-10-29 | Kirin Pharma K K | Chinolinderivat und chinazolinderivat, die die selbstphosphorylierung des hepatocytus-proliferator-rezeptors hemmen, und diese enthaltende medizinische zusammensetzung |
JO2311B1 (en) * | 2001-08-29 | 2005-09-12 | ميرك فروست كندا ليمتد | Alkyl inhibitors Ariel phosphodiesterase-4 |
AU2003249212C1 (en) * | 2002-07-15 | 2011-10-27 | Symphony Evolution, Inc. | Receptor-type kinase modulators and methods of use |
US7560558B2 (en) * | 2002-08-23 | 2009-07-14 | Kirin Beer Kabushiki Kaisha | Compound having TGFβ inhibitory activity and medicinal composition containing the same |
EP1566379A4 (de) * | 2002-10-29 | 2005-11-09 | Kirin Brewery | CHINOLINDERIVATE UND CHINAZOLINDERIVATE ALS HEMMER DER Flt3-AUTOPHOSPHORYLIERUNG UND DIESE ENTHALTENDE MEDIZINISCHE ZUSAMMENSETZUNGEN |
WO2004072117A2 (en) | 2003-02-13 | 2004-08-26 | Pharmacia Corporation | Antibodies to c-met for the treatment of cancers |
EP2093570A1 (de) | 2003-06-06 | 2009-08-26 | Genentech, Inc. | Modulierung der Interaktion zwischen HGF-beta-Kette und c-Met |
ES2371383T3 (es) * | 2003-09-26 | 2011-12-30 | Exelixis, Inc. | N-[3-fluoro-4-({6-(metiloxi)-7-[(3-morfolin-4-ilpropil)oxi]quinolin-4-il}oxi)fenil]-n'-(4-fluorofenil)ciclopropan-1,1-dicarboxamida para el tratamiento del cáncer. |
WO2005094805A1 (ja) * | 2004-04-01 | 2005-10-13 | Institute Of Medicinal Molecular Design. Inc. | イミン誘導体及びアミド誘導体 |
JO2787B1 (en) * | 2005-04-27 | 2014-03-15 | امجين إنك, | Alternative amide derivatives and methods of use |
WO2007146824A2 (en) | 2006-06-08 | 2007-12-21 | Array Biopharma Inc. | Quinoline compounds and methods of use |
CN101516379A (zh) | 2006-09-14 | 2009-08-26 | 迪赛孚尔制药有限公司 | 可用于治疗增殖性疾病的激酶抑制剂 |
EP2201010B1 (de) * | 2007-09-14 | 2013-11-06 | Vertex Pharmaceuticals Incorporated | Modulatoren des cystic fibrosis transmembrane conductance regulator |
WO2012011548A1 (ja) * | 2010-07-23 | 2012-01-26 | 国立大学法人 東京大学 | 含窒素複素環誘導体 |
AU2012223639B2 (en) * | 2011-02-28 | 2015-03-19 | Sunshine Lake Pharma Co., Ltd. | Substituted quinoline compounds and methods of use |
EP2780338B1 (de) * | 2011-11-14 | 2016-11-09 | Ignyta, Inc. | Uracilderivate als axl- und c-met-kinaseinhibitoren |
CN102643268B (zh) * | 2011-12-30 | 2014-05-21 | 沈阳药科大学 | 喹啉类及噌啉类化合物及其应用 |
WO2013143376A1 (zh) * | 2012-03-26 | 2013-10-03 | 武汉盛云生物医药科技有限责任公司 | 含1,2,4-三嗪-3,5-二酮的喹啉类化合物及其应用 |
CN102977014B (zh) * | 2012-11-05 | 2015-01-07 | 沈阳药科大学 | 新的喹啉类化合物及其用途 |
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- 2012-12-07 JP JP2014549298A patent/JP6087954B2/ja not_active Expired - Fee Related
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WO2013097280A1 (zh) | 2013-07-04 |
US9382232B2 (en) | 2016-07-05 |
US20140364431A1 (en) | 2014-12-11 |
CN102643268A (zh) | 2012-08-22 |
JP6087954B2 (ja) | 2017-03-01 |
JP2015503528A (ja) | 2015-02-02 |
CN102643268B (zh) | 2014-05-21 |
EP2799437B1 (de) | 2016-09-14 |
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